Research over the past decades has sought to elucidate the neurobiological causes of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). More recently, there is increasing interest into the relationship of co-morbid PTSD and MDD given their high rates of co-occurrence and the clinical challenges found in this severely ill patient population. Ligand-based imaging techniques, while more widely applied to PTSD and MDD alone, have not been utilized to examine systematically their co-occurrence. The proposed translational research study aims to expand current knowledge of the neurobiological mechanisms of the co-occurrence of PTSD and MDD using state-of-the-art brain imaging techniques with positron emission tomography (PET) on a high resolution research tomograph (HRRT) and a novel radioligand for the serotonin (5-HT) 1B receptor. A growing body of evidence suggests that the 5-HT1B receptor might play an important role in the etiology of mood and anxiety disorders, and potentially also in their co-occurrence. The 5-HT1B receptor plays a central role in the regulation of serotonin (5-HT) transmission, mesocorticolimbic circuitry functioning and in the pathophysiology of mood and anxiety disorders. As selective ligands for the 5-HT1B receptor have only recently become available, knowledge for the involvement of 5-HT1B receptors in these disorders is still limited. Thus, in vivo quantitation of the density and distribution of 5-HT1B receptors might provide important insights into mechanisms contributing to the co-morbidity of PTSD and MDD. The Yale Positron Emission Tomography (PET) Center has been a pioneer in the development of a PET radiotracer selective for 5-HT1B receptors. We propose to apply this innovative ligand to study for the first time systematically the co-occurrence of PTSD and MDD. We propose using [11C]P943, a selective, high affinity 5- HT1B receptor antagonist, to investigate 5-HT1B receptor binding potential (BPND) in PTSD subjects with co-morbid MDD and MDD subjects without history of trauma. We will also compare their data to cohorts of patients with PTSD without MDD and healthy control subjects which have been collected under a different grant mechanism. We believe that this study will generate important novel results which will inform us about the neurobiological mechanisms associated with co-morbid PTSD and MDD. In addition, the results derived from this research has the potential to inform the development of treatment procedures that are directed specifically to co-morbid symptoms, guide initial dosing of new therapeutic agents and that are central to predict symptom onset, monitor disease progression and assess the efficacy of therapeutic agents. PUBLIC HEALTH RELEVANCE: The neurotransmitter serotonin plays an important role in the development of post-traumatic stress disorder (PTSD) and depression. With the use of positron emission tomography (PET) and administration of a radiotracer, we are able to measure the distribution of serotonin type 1B receptors in the brain. This method allows to determining whether people with PTSD and depression show a different number of serotonin 1b receptors in the brain as compared to healthy people without PTSD and depression and people with only depression.